A recent review article by Hawthorne (Angew. Chem. Int. Ed. Engl., 1993, 32:950) describes boron neutron capture therapy for cancer (see, also, Barth et al., Scientific American, 1990, Oct.:100). The use of boron compounds in the treatment of cancer is based on the unique affinity of nonradioactive .sup.10 B nuclei for thermal (low-energy) neutrons to produce, by nuclear (n,.alpha.) reaction (via unstable .sup.11 B), an .alpha.-particle and a lithium-7 particle ion with a kinetic energy of 2.31 MeV. Thus, reactants of very low energy (less than 1-2 KeV) are converted to cytotoxic products of 2.31 MeV directly within the target (such as a cancerous) cell. Since the nuclear fragments produced by this fission reaction have mean free paths for reaction with tissue that are on the order of only 5 .mu.m (.sup.7 Li) and 9 .mu.m (.sup.4 He), or one cell diameter, destructive radiation predominates only in the immediate vicinity of cells containing significant .sup.10 B concentrations. When this event takes place at a neoplastic lesion, one has the basis for a preferential tumor treatment.
Specifically, boron neutron capture therapy (BNCT) is a binary therapy: it relies on the use of a .sup.10 B-labeled substance that localizes preferentially in or near tumor sites, and on the irradiation of said .sup.10 B-rich sites with externally generated slow neutrons. Both of these apparently are required for success. Indeed, failures in early BNCT studies were attributed to an inadequate concentration of .sup.10 B at the cancerous sites and/or a lack of selectivity in the disposition of the .sup.10 B-containing material.
In the last two decades treatment of brain tumors using BNCT has been performed in Japan using improved boron compounds and neutron irradiation techniques. Promising results have been obtained and interest in BNCT is increasing. A major problem that remains, however, in BNCT is that associated with delivering large quantities of boron to the target structure via means of an effective and convenient carrier system. It is now clear that success in the BNCT field will require that sufficient quantities of .sup.10 B be delivered to the cancer cell so as to be able to sustain lethal reactions.
It has been calculated that an effective dose of .sup.10 B in a tumor should be in the range of 5-30 ppm. Thus, a one-fold boronated compound (i.e., a mono-boron containing species) will not meet this stringent criterion for BNCT. Compounds that make use of carborane clusters, which have a high inherent boron content, should be more effective, provided, of course, that efficient and selective uptake of the boron-containing carrier molecules by cancer or other target cells can be attained. Examples of carborane clusters are the icosahedral closo-C.sub.2 B.sub.10 H.sub.12 carboranes (such as 1,2-dicarba-closo-dodecaborane (o-carborane, 1a), 1,7-dicarba-closo-dodecaborane (m-carborane, 1b), and 1,12-dicarba-closo-dodecaborane (p-carborane, 1c)) as well as other carboranes of the general formula closo-C.sub.2 B.sub.n-2 H.sub.n, where n=6 through 12, and the corresponding closo-CB.sub.n-1 H.sub.n --carborane series. ##STR1##
Many porphyrins and porphyrinoid compounds have demonstrated an ability to selectively accumulate in tumors, and have therefore been considered as possible candidates for delivery of boron to malignant tissue (see, U.S. Pat. Nos. 4,959,356 and 5,149,801; Kahl et al., Basic Life Sci., 1989, 50:325; Miura et al., Tetrahedron Lett., 1990). However, no carboranyl or other boronated "expanded porphyrins" have been known or suggested.
The texaphyrins are aromatic pentadentate macrocyclic expanded porphyrins which have been found to be useful as MRI contrast agents, as radiation sensitizers and in photodynamic therapy (PDT). Texaphyrin is considered as being an aromatic benzannulene containing both 18.pi.- and 22.pi.-electron delocalization pathways. See, e.g., Sessler, J. L. et al., Accounts of Chemical Research, 1994, 27, 43. Texaphyrins and water-soluble texaphyrins and methods of preparation have been described in, for example, U.S. Pat. Nos. 4,935,498; 5,252,720; 5,256,399; 5,272,142; 5,292,414; 5,457,183; 5,583,220; and 5,599,923; all of which are incorporated herein by reference.
The sapphyrins are 22.pi.-electron pentapyrrolic macrocyclic expanded porphyrins which are useful for PDT, as anion chelating agents, and in the separation of nucleotides and oligonucleotides. Sapphyrins and water-soluble sapphyrins and methods of preparation have been described in, for example, U.S. Pat. Nos. 5,041,078; 5,120,411; 5,159,065; 5,302,714; 5,457,195; and 5,543,514; and in PCT Publication No. WO 94/09003; all of which are incorporated herein by reference.